Evaluating Small Arteries in the Brain: The Effects of Hypertension and Diabetes

Guy M. McKhann, M.D.

Johns Hopkins University

Funded in September, 2010: $100000 for 1 years

Evaluating small arteries in the brain: The effects of hypertension and diabetes

Investigators will conduct pilot tests in patients to determine whether a new imaging technique can help to differentiate brain signs of cognitive impairment and dementia associated with Alzheimer’s disease from those associated with underlying vascular disease. They will see, in patients with coronary heart disease, whether the imaging technique enables them to correlate the extent of damage to small blood vessels in the brain with the degree of patients’ cognitive impairment.

Efforts to determine the validity of this new imaging technique in cognitively impaired patients build upon findings by Dr. McKhann and colleagues that cognitive impairment, anecdotally linked to coronary artery bypass grafting (CABG) surgery, is attributable to underlying vascular disease and not to CABG surgery. The conclusive findings were the first to include a heart-healthy control group with no cardiovascular risk factors, and compared cognitive performance of patients, at baseline and up to 72 months thereafter, who were treated: (1) with CABG surgery using a heart-lung machine to pump oxygen-rich blood to the brain while their hearts were stopped; (2) with CABG surgery performed without stopping the heart and no pump; and (3) non-surgically, with medical drugs. All three patient groups with coronary artery disease, regardless of type of therapy, performed similarly on cognitive tests. At baseline, patients had lower cognitive performance compared to the heart-healthy control group, especially in the subcortical areas of motor speed and “psychomotor” speed (hearing, processing and initiating movement in response to a command). At post-operative periods of up to 72 months, patients showed progressive cognitive decline. The lower baseline performance and progressive cognitive decline are attributed to underlying cerebrovascular disease. Further, the cognitive changes were disproportionately associated with these subcortical changes, changes associated with underlying vascular disease.

While vascular dementia is less well recognized and studied compared to Alzheimer’s dementia, recent research has established that cerebrovascular disease and Alzheimer’s disease co-exist in many patients. Moreover, the combination of both disease processes in the brain, called “mixed dementia,” produces more severe cognitive consequences than would be anticipated with either disease process alone. While Alzheimer’s cannot yet be prevented, many risk factors associated with vascular disease—such as hypertension, diabetes and smoking—can be avoided. Better understanding of the processes in the brain associated with underlying vascular disease and associated cognitive impairment may lead to improved strategies for prevention or treatment.

While imaging techniques have become increasingly more effective in identifying occlusions (blockages causing stroke) in large blood vessels in the brain and damage to nearby brain tissues deprived of oxygen, cerebrovascular disease associated diabetes and hypertension affect smaller arteries in the brain, where the innermost walls of small arteries become thickened and even occluded. While these changes are documented through autopsy studies, they are not adequately evaluated by current imaging techniques.

While MRI is commonly used in patients with cognitive impairment to identify structural evidence of vascular dementia (large infarcts), functional blood flow measures may be more sensitive to identifying disease in the brain’s small blood vessels. A newly developed imaging technique that measures cerebrovascular reactivity (CVR)—dilation of small blood vessels in response to carbon dioxide—may enable researchers to quantitatively evaluate small vessel blood flow and demonstrate cerebrovascular disease in the brain.

Small blood vessels damaged in Alzheimer’s disease, unlike those damaged by hypertension or diabetes, can dilate (expand) when challenged with carbon dioxide. Small blood vessels that do not dilate, therefore, are damaged by underlying cerebrovascular disease, not Alzheimer’s. The CVR technique may be able to evaluate cerebrovascular disease in dementia, differentiating vascular dementia from Alzheimer’s dementia, and may lead to modifying the vascular disease process.

This technique consists of administering carbon dioxide during a brain MRI exam. Cerebrovascular reactivity is measured through changes in the Blood Oxygen Level Dependent (BOLD) MRI signal. The technique has been shown to be useful clinically, easily administered, safe, and reproducible. The machine, called Respiract® was developed by University of Toronto investigators, and a member of the Hopkins research group was trained there to use it.

Imaging will be undertaken in participants of the prior CABG study, for whom there are already baseline and long-term cognitive measures. Participants will include 13 patients who underwent CABG surgery and showed the greatest cognitive decline, and two groups of age-matched controls: 13 patients who underwent CABG surgery and showed the least cognitive decline, and 13 of the heart-healthy volunteers. The investigators then will re-image four participants from each of the three groups two months later to measure the technique’s reproducibility.

The initial sample is small, but the pilot study will enable the investigators to compare patients with the greatest cognitive impairments to those with little impairment, and against a healthy control group. They anticipate that patients with the greatest cognitive impairment will show: (1) reduced cardiovascular reactivity, indicative of cerebrovascular damage to small blood vessels; (2) structural evidence of cerebral small vessel disease—white matter disease and infarcts; and (3) reduced cerebral volumes. They also expect cardiovascular reactivity measurements to be associated with small vessel disease risk factors (hypertension and diabetes).

Significance: If the technique is validated through larger studies, the findings from this pilot study will have broad implications for identifying vascular dementia and differentiating it from Alzheimer’s dementia, leading to improved intervention to treat or reverse the cerebrovascular disease process in the brain.